Diabetic nephropathy is the leading cause of end stage renal disease in spite of improvements in therapy over the last 20 years. The identification of a biomarker that can predict which patients will lose renal function would enable better treatment for these patients. Available markers such as urinary albumin are neither sensitive nor specific. We identified urinary haptoglobin concentration as a candidate biomarker which can predict development of renal functional decline among patients with diabetes who do not yet show signs of disease. We propose to characterize the role of haptoglobin as a biomarker for the prediction of renal functional decline. The specific aims of this proposal are: 1) Determine the ability of urinary haptoglobin and other candidate biomarkers to predict early renal functional decline in patients with type 2 diabetes who have normal renal function and do not have macroalbuminuria, 2) Assess the ability of haptoglobin and other candidate biomarkers measured in serial collections of urine to predict ERFD and 3) Determine the ability of urinary haptoglobin and other candidate biomarkers to predict progression of existing diabetic kidney disease. We will use urine samples that were collected prospectively as part of the VA Glycemic Control and Complications in Diabetes Mellitus Type 2 trial (VADT). The VADT includes 1,700 subjects randomized to either intensive or conventional therapy. Follow up was at least 5 years. Mean duration of diabetes at enrollment was 11.1 years. We will use a subset of this population that includes 987 patients. We will also use prospectively collected samples to assess the ability of biomarkers to predict progression of existing kidney disease. We propose to use multiple reaction monitoring (a mass spectrometric analysis of abundance based on a stable isotopic standard) to measure urine haptoglobin concentrations as well as the concentration of a panel of additional candidate biomarkers. We will measure concentrations in serially collected samples from the VADT cohort and from the prospectively collected samples. These studies will define the ability of urine haptoglobin to predict the future development of renal functional decline in subjects without (aims 1 and 2) and with (aim 3) existing renal disease.